Shinichi Nakao

Pentobarbital inhibits ketamine-induced dopamine release in the rat nucleus accumbens: A microdialysis study

UNLABELLED Dopamine release in the nucleus accumbens (NAC) plays a crucial role in the actions of various psychotropic and addictive drugs. Ketamine and barbiturates have psychotropic effects and addictive properties, but barbiturates prevent ketamines psychotomimetic effects. We investigated the effects of ketamine and pentobarbital on dopamine release in the NAC. A microdialysis probe was implanted in the NAC in 35 rats, which were randomly assigned to seven groups: a normal saline intraperitoneal injection (ip) group, 50 and 100 mg/kg of ketamine ip groups, 25 and 50 mg/kg of pentobarbital ip groups, and a normal saline or 25 mg/kg of pentobarbital ip followed by 50 mg/kg of ketamine ip groups. Perfusate samples were collected every 20 min, and dopamine concentration was measured by high-performance liquid chromatography. Ketamine at doses of 50 mg/kg and 100 mg/kg significantly increased dopamine release in the NAC. Conversely, pentobarbital significantly decreased dopamine release in the NAC and inhibited the ketamine-induced dopamine release. These data suggest that the dopamine release in the NAC may be involved in ketamine-induced, but not barbiturate-induced, psychotropic effects and addiction. Inhibition of ketamine-induced dopamine release by barbiturates may be a mechanism by which they prevent ketamine emergence reactions. IMPLICATIONS Ketamine increased dopamine release in the nucleus accumbens, which was inhibited by pentobarbital. The mesolimbic dopamine system may be involved in the psychotomimetic effects of ketamine, and the suppression of ketamine emergence reactions by barbiturates may be because of the inhibition of ketamine-induced dopamine release in the nucleus accumbens.

Xenon Inhibits but N2o Enhances Ketamine-induced c-fos Expression in the Rat Posterior Cingulate and Retrosplenial Cortices

Both nitrous oxide (N2O) and xenon are N-methyl-d-aspartate receptor antagonists that have psychotomimetic effects and cause neuronal injuries in the posterior cingulate and retrosplenial cortices. We investigated the effect of xenon, xenon with ketamine, N2O, and N2O with ketamine on c-Fos expression in the rat posterior cingulate and retrosplenial cortices, a marker of psychotomimetic effects. Brain sections were prepared, and c-Fos expression was detected with immunohistochemical methods. A loss of microtubule-associated protein 2, a marker of neuronal injury, was also investigated. The number of Fos-like immunoreactivity positive cells by ketamine IV at a dose of 5 mg/kg under 70% N2O (128 ± 12 cells per 0.5 mm2) was significantly more than those under 30% (15 ± 2 cells per 0.5 mm2) and 70% xenon (2 ± 1 cells per 0.5 mm2). Despite differences in c-fos immunoreactivity, there was no loss of microtubule-associated protein 2 immunoreactivity in any group examined. Xenon may suppress the adverse neuronal effects of ketamine, and combined use of xenon and ketamine seems to be safe in respect to neuronal adverse effects. Implications Xenon may suppress adverse neuronal effects of ketamine. Conversely, combined use of N2O and ketamine may increase the risk of neuronal adverse effects, such as psychotomimetic effects.

Inhibitory effect of propofol on ketamine‐induced c‐Fos expression in the rat posterior cingulate and retrosplenial cortices is mediated by GABAA receptor activation

Background:  Non‐competitive N‐methyl‐D‐aspartate (NMDA) receptor antagonists, including ketamine, have psychotomimetic activities and cause neuronal damage in the posterior cingulate and retrosplenial cortices (PC/RS), which are suggested to be the brain regions responsible for their psychotomimetic activities. We previously demonstrated that ketamine induced marked c‐Fos (c‐fos protein) expression in the rat PC/RS, which was inhibited by propofol, and the expression was closely related to ketamine‐induced abnormal behavior. In the present study, we investigated whether the inhibition by propofol was mediated by GABAA receptor receptor activation.

The effect of ketamine isomers on both mice behavioral responses and c-Fos expression in the posterior cingulate and retrosplenial cortices.

Ketamine, a non-competitive NMDA receptor antagonist, is a racemic mixture. S(+) ketamine is presumed to be more potent as an anesthetic than R(-) ketamine, and causes less postanesthetic stimulation of locomotor activity than R(-) ketamine in animals at equihypnotic doses. In the present study, we investigated the effect of S(+), R(-), and racemic ketamines on mice behavioral responses and c-Fos expression in the posterior cingulate and retrosplenial cortices (PC/RS), which are suggested to be the brain regions responsible for NMDA-receptor-antagonist-induced psychotomimetic activity. Ataxia and head weaving and c-Fos expression in the PC/RS were significantly more induced by both S(+) and racemic ketamines than by R(-) ketamine at the same dose. S(+) ketamine induced significantly more potent ataxia than racemic ketamine at the same dose. Ketamine-induced c-Fos expression in the PC/RS correlated well with the intensity of behavioral responses. These results imply that R(-) ketamine is weaker than both S(+) and racemic ketamines in a psychotomimetic effect. Also, S(+) ketamine is more potent than racemic ketamine in a psychotomimetic effect and possibly in an anesthetic effect. They also indicate that PC/RS is at least one of the specific brain regions responsible for ketamine-induced behavioral responses in animals and a psychotomimetic activity in humans.

Edaravone, a free radical scavenger, mitigates both gray and white matter damages after global cerebral ischemia in rats.

Recent studies have shown that similar to cerebral gray matter (mainly composed of neuronal perikarya), white matter (composed of axons and glias) is vulnerable to ischemia. Edaravone, a free radical scavenger, has neuroprotective effects against focal cerebral ischemia even in humans. In this study, we investigated the time course and the severity of both gray and white matter damage following global cerebral ischemia by cardiac arrest, and examined whether edaravone protected the gray and the white matter. Male Sprague-Dawley rats were used. Global cerebral ischemia was induced by 5 min of cardiac arrest and resuscitation (CAR). Edaravone, 3 mg/kg, was administered intravenously either immediately or 60 min after CAR. The morphological damage was assessed by cresyl violet staining. The microtubule-associated protein 2 (a maker of neuronal perikarya and dendrites), the beta amyloid precursor protein (the accumulation of which is a maker of axonal damage), and the ionized calcium binding adaptor molecule 1 (a marker of microglia) were stained for immunohistochemical analysis. Significant neuronal perikaryal damage and marked microglial activation were observed in the hippocampal CA1 region with little axonal damage one week after CAR. Two weeks after CAR, the perikaryal damage and microglial activation were unchanged, but obvious axonal damage occurred. Administration of edaravone 60 min after CAR significantly mitigated the perikaryal damage, the axonal damage, and the microglial activation. Our results show that axonal damage develops slower than perikaryal damage and that edaravone can protect both gray and white matter after CAR in rats.

Ketamine-induced c-Fos expression in the mouse posterior cingulate and retrosplenial cortices is mediated not only via NMDA receptors but also via sigma receptors.

Ketamine induces marked c-fos expression in the posterior cingulate and retrosplenial cortices (PC/RS). We investigated whether NMDA and/or sigma receptors were involved in the c-Fos expression. The number of Fos-LI positive boutons in NMDA receptor knockout mice was significantly lower than that in wild-type mice. Rimcazole but not haloperidol significantly suppressed the c-Fos expression. The results indicate that the ketamine-induced c-Fos expression is mediated not only via NMDA receptors but also via sigma receptors.

Role of mitochondrial KATP channels and protein kinase C in ischaemic preconditioning.

1. Activation of mitochondrial KATP (mitoKATP) channels and protein kinase C (PKC) has been implicated in cardioprotective mechanisms of ischaemic preconditioning (IPC). However, the exact role of these events in early IPC remains unclear.

Propofol depressed neutrophil hydrogen peroxide production more than midazolam, whereas adhesion molecule expression was minimally affected by both anesthetics in rats with abdominal sepsis.

The treatment of sepsis may require mechanical ventilation of the lungs and sedation. Because neutrophils are the most important effector cells for protecting against sepsis, and propofol and midazolam are the most widely used anesthetics for sedation, we studied the effects of these two anesthetics on the neutrophil function during sepsis. Sepsis was induced in rats by cecal ligation and puncture. At either 4 h or 24 h after cecal ligation and puncture, blood and peritoneal neutrophils were obtained, incubated with the test anesthetics, and the hydrogen peroxide (H2O2) production and CD11b/c expression were determined by flow cytometry. In both early (at 4 h) and late (at 24 h) sepsis, propofol and midazolam depressed H2O2 production by blood and peritoneal neutrophils at clinical concentrations. Propofol caused more depression than midazolam (P < 0.005). In both early and late sepsis, the effect of the anesthetics on the up-regulation of the stimulation-induced CD11b/c expression on blood neutrophils was minimal at clinical concentrations. If these results ultimately become clinically relevant, midazolam may be preferable to propofol for sedation during sepsis. Implications In septic patients, mechanical ventilation of the lungs is sometimes needed, and propofol and midazolam are widely used for sedation. Midazolam was less inhibitory for neutrophil function than propofol during sepsis; thus, midazolam may be preferable to propofol for sedation during sepsis for preserving the neutrophil function to combat sepsis.

Integrated pharmacological preconditioning in combination with adenosine, a mitochondrial KATP channel opener and a nitric oxide donor.

BACKGROUND Mitochondrial K(ATP) channel activation is an essential component of ischemic preconditioning. These channels are selectively opened by diazoxide and may be up-regulated by adenosine and nitric oxide. Therefore, pharmacological preconditioning with diazoxide in combination with adenosine and a nitric oxide donor (triple-combination pharmacological preconditioning) may enhance cardioprotection. METHODS AND RESULTS Isolated and perfused rat hearts underwent ischemic preconditioning with 3 cycles of 5 minutes of ischemia and 5 minutes of reperfusion before 5 minutes of oxygenated potassium cardioplegia and 35 minutes of ischemia. Pharmacological preconditioning was performed by adding adenosine, diazoxide, and a nitric oxide donor S-nitroso-N-acetyl-penicillamine each alone or in combinations for 25 minutes followed by 10 minutes washout before cardioplegic arrest. Only triple-combination pharmacological preconditioning conferred significant cardioprotection as documented by highly improved left ventricular function and limited creatine kinase release during reperfusion that was comparable to that afforded by ischemic preconditioning. Mitochondrial K(ATP) channel activity assessed by flavoprotein oxidation was increased by diazoxide, but no further increase in flavoprotein oxidation was obtained by ischemic preconditioning and triple-combination pharmacological preconditioning. Significant activation of protein kinase C-epsilon was observed in only ischemic preconditioning and triple-combination pharmacological preconditioning. Pretreatment with the mitochondrial K(ATP) channel inhibitor 5-hydroxydecanoate or the protein kinase C inhibitor chelerythrine abrogated activation of protein kinase C-epsilon and cardioprotection afforded by ischemic preconditioning and triple-combination pharmacological preconditioning. CONCLUSIONS Integrated pharmacological preconditioning is not simply mediated by enhanced mitochondrial K(ATP) channel activation, but is presumably mediated through amplified protein kinase C signaling promoted by coordinated interaction of adenosine, mitochondrial K(ATP) channel activation, and nitric oxide.

Successful management of cesarean section in a patient with Romano-Ward syndrome using landiolol, a selective and short-acting β1 receptor antagonist

Romano–Ward (R-W) syndrome is an autosomal dominant hereditary disorder and is characterized by a prolonged QT interval on the electrocardiogram (ECG), syncope, and sudden death. We report here a case of cesarian section in a patient with R-W syndrome whose QT prolongation was successfully managed with landiolol, a selective β1 receptor blocker. A 25-year-old woman with R-W syndrome was scheduled for cesarean section. In the operating room, the patient’s ECG showed tachycardia (102 beats·min−1) and marked QT prolongation (QTc = 0.56 s). After spinal anesthesia, the patient’s heart rate (HR) increased to 130 beats/min accompanied by a slight decrease in arterial blood pressure to 97/57 mmHg and the QTc was prolonged to 0.57 s. Landiolol was continuously infused at a rate of 0.04 mg·kg−1·min−1 and the HR gradually decreased to 80–90 beats·min−1 accompanied by the normalization of QTc to 0.48 s. We thought that the use of landiolol was more rational and was preferable to a nonselective β receptor blocker for a term-pregnant woman because blockade of the β2 receptor might cause uterine contraction. After the use of landiolol, intraoperative and postoperative courses in both the patient and the baby were uneventful.